In addition, the PANDRH-GCPs definition further states that an IP may include a product with a marketing authorization when it is used or assembled formulated or packaged in a different way from the approved form, or when it is used to gain further information about an approved use.
Note: The terms experimental drug and IP are used interchangeably throughout the profile. COPEC will then analyze the following:. See Submission Process and Submission Content sections for detailed application requirements. ResNo81 explains that the following documentation must be included with the petition:. See also BRA-8 for frequently asked questions on importation requirements. Per ResNo , ANVISA will analyze and release imported goods and products intended for use in human subject research within 48 hours after arrival in Brazil, provided that the legal requirements are met and that the purpose of the research is not to register or change the registration of a product.
Refer to ResNo81 for additional required items depending on the import method used. Generally, the DSI is used for samples with no commercial value. Per ResNo , researchers accredited by the National Council for Scientific and Technological Development CNPq and whose tax regime is exempt, will be automatically granted an import license via the Integrated Foreign Trade System Siscomex BRA for imported goods and products intended for use in human subject research.
The import requirements described in the previous paragraphs do not apply to research involving human beings whose purpose is to register or change the registration of the product under research.
ResNo specifies that imports intended for clinical trials whose objective is registration or alteration of product registration will be analyzed within five 5 days after protocol approval and compliance with legal requirements.
Other requirements delineated in ResNo81 and ResNo include, but are not limited to, a prohibition on imports with accompanied and unaccompanied baggage; compliance with packaging, transportation, and storage standards provided by manufacturer or supplier; and a mandate that once research is completed, the researcher or institution authorize final destination of the materials in accordance with the legal provisions of environmental control.
This exemption will only be valid for up to three 3 years. Following this period, the product must be registered or be subject to a penalty of seizure to be determined by the MOH. In addition, per ResNo , in the case of a company requesting a global transfer of ownership for product registration or the updating of company operation and certification data as a result of corporate transactions or business operations, the CE, CEE, or Document for Importation of Product s under Investigation will be issued in the name of the new company.
Please refer to ResNo for detailed instructions on submitting appropriate documentation for these updates. The IB must contain all of the relevant information on the investigational product s IPs obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor should also update the IB as significant new information becomes available.
See also BRA for guidelines on conducting non-clinical toxicology and pharmacological safety studies required during drug development. Investigator's Brochure Content Requirements. The sponsor is also accountable for supplying the IP, including the comparator s and placebo, if applicable.
See ResNo for detailed submission information. See Product Management section for additional information on IP supply, storage, and handling requirements. As described in the G-BiolProdManual , the following labeling information must be included on the primary package label or any intermediate packaging , and the outer packaging:. Symbols, pictograms, and warnings may also be included on both the primary and outer packaging. The trial participant receives a leaflet or card containing contact information in the case of trial-related concerns or adverse events.
If the expiration date changes, additional labeling may be superimposed on the previous label to update the shelf life so that the new information does not conflict with the original batch number. The G-BiolProdManual mentions that the labeling of the other study IPs should also follow the same model as the experimental product, and when any field s is not applicable, justification should be provided. The PANDRH-GCPs further indicates that the IP should be coded and labeled in a manner that protects the blinding, if applicable, and be suitably packaged to prevent contamination and unacceptable deterioration during transport and storage.
As described in ResNo9 , the following external packaging information must also be provided with the IP to be imported into Brazil:. See the Submission Process and Submission Content sections for detailed application requirements. Finally, the sponsor should maintain sufficient samples from each batch and keep a record of their analyses and characteristics for reference so that, if necessary, an independent laboratory could reconfirm the same data. The sponsor should inform the investigator s and institution s in writing of the need for record retention and should notify the investigator s and institution s in writing when the trial-related records are no longer needed.
As per OrdNo , ResNo , ResNo , and the G-BiolMatTransprt , a specimen is defined as any human biological material such as organs, tissues, cells, body fluids, excreta, and other fluids of human origin obtained from a single participant at a particular time.
ResNo adds that these biological samples are intended to be used for laboratory or quality control tests. In addition, the G-BiolMatTransprt states that these materials are not considered hazardous if they are unlikely to cause disease in humans or animals.
However, they are considered infectious substances, therefore dangerous materials, if through exposure to them, these substances are capable of spreading diseases. ResNo81 and ResNo delineate the procedures associated with importing human biological materials for clinical research purposes. ResNo81 and ResNo explain that the following documentation must be included with the petition form:. ResNo also states that ANVISA will analyze and release human biological samples intended for use in clinical research within 48 hours after arrival in Brazil, provided that the legal requirements are met.
Refer to ResNo81 and ResNo for additional required items depending on the import method used. Generally, DSI is used for samples with no commercial value. Other requirements described in ResNo81 and ResNo include, but are not limited to, compliance with packaging, transportation, and storage standards provided by manufacturer or supplier; a mandate that the researcher or institution give final destination to the materials in accordance with the legal provisions of environmental control; and, in ResNo , a prohibition on imports with accompanied and unaccompanied baggage.
As explained in ResNo and the G-BiolMatTransprt , the procedures for the import and export of human biological material should be determined by the biological material type and the mode of transport. Regardless of the mode of transport or material type, transport operations are required to be recorded and standardized through regularly updated written instructions.
All documents and records of activities relating to human biological material transport equipment should be readily available to the health authorities, upon request. The biological material must be packed in a form that will preserve its integrity and stability and must be validated and approved by the supervisory technician. Category A includes materials where exposure can cause permanent disability or fatal disease to humans and animals. Category B includes those materials not listed in Category A such as samples suspected or known to contain infectious agents causing diseases in humans.
Labeling should conform to the material type, risk classification, and specific requirements of the biological materials to be transported.
The label for imported materials must be legible, understandable, and in English and Portuguese. In addition to complying with ResNo and the G-BiolMatTransprt , human biological material transport should be conducted in accordance with legislation from applicable regulatory bodies including the Ministry of Transport, the National Land Transportation Agency, the National Civil Aviation Agency, and the National Agency of Waterway Transportation.
Refer to the G-BiolMatTransprt for detailed import and export transport requirements. Refer to ResNo and the G-BiolMatTransprt for detailed instructions on shipping biological materials within these categories.
See also ResNo for detailed transport requirements relating to human cells and advanced research therapy products. If it is impossible to obtain either one 1 of these documents, this fact shall be justified to the EC CEP. OrdNo also states that when it is not possible to contact the research participant, the EC CEP must authorize use of the biological material stored in a biobank. CLNo further notes that for human genetics research, CONEP requires investigator s to be able to describe the genes studied in a grouped manner according to functionality or effect e.
In the case of studies involving large-scale genetic studies e. The withdrawal is valid from the date that the decision is communicated.
In addition, the transfer of human biological material to be stored at a biorepository or a biobank, or another institution, must be communicated to the participant. Please refer to OrdNo , ResNo , and the G-ClinProtocols-FAQs , for detailed requirements and issues associated with storing human biological materials in a biorepository or a biobank.
See also ResNo for informed consent requirements pertaining to human cell collection and other procedures conducted by cell processing centers. See the Required Elements and Participant Rights sections for additional information on informed consent. Details on the most recent Brazil updates are available here.
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Consent for Specimen. Additional Resources. View recent profile updates View all sources. Articles , , and Chapter I Articles 1 and 2. Articles , , , 63, 88, 91, 97, , , and Annex III. According to ServBltnNo , the IP manufacturing process must also meet the criteria and recommendations described in the ICH guidelines, as applicable, according to the phase of clinical development. COPEC will then analyze: the results of stability studies under accelerated and long-term conditions that support the proposed expiration date for the IP and, where applicable, for the modified placebo and comparator, when the storage recommendation is at room temperature between 15 and 30 degrees Celsius ; and the sample IP label, for DDCM petitions.
Preamble and I. Article Sections VI-XI. Articles 1, , and Articles Articles 91, , and Annex III. Chapters 2 2. Conducting a Clinical Trial in Brasil. Introduction and Regulatory Framework. Articles 6 and 7. Articles 2, 9, 14, and Chapter III Article Articles 2, 9, and Annex I 4.
Article 1. Chapter I. Preamble, Articles 1 and Definition of Health Council. Sections VI-X. Sections 2, 3, and Let's Talk about Plataforma Brazil.
IV and VI. Preamble and Articles 1 and Articles 1 and I and III-V. Article 9. Section VII. I and II. Local Accreditation. Changes potentially impacting the quality or safety of the IP, active comparator, or placebo are equivalent to substantial changes in quality. Heterogeneity of insurance and indemnification requirements is a common issue that needs to be considered while conducting an international trial.
Study compliance often requires coverage by a local malpractice insurance policy that provides negligent-harm coverage for investigators. Some noncommercial insurance policies may only cover non-negligent harm only or contain other restrictions, such as refusing coverage for HIV studies, certain geographic areas, or children.
As a result, regional or global standardized indemnification and insurance requirements, which may be trial-specific or group-specific, could benefit research infrastructure [e. However, funding insurance premiums for such a standardized model across country borders could be a limiting factor. As more clinical trials assume an international scope, regulatory authorities in all countries need to recognize and address these major hurdles in multinational investigation.
The regulatory burden contributes to protracted timelines that potentially impact the relevance of the scientific question being addressed. Such delays could that negatively influence enthusiasm at sites and bias the recruitment of countries participating in the study.
Obtaining adequate financing is an ever-present issue in clinical trials and in science in general. Sponsors desire efficiency without compromising data quality. Investigators generally accept the cost structure of the trial when it is presented or choose to not participate.
There are many models of payment, but in a typical arrangement, the clinical or data coordinating center oversees the issuance of subcontracts to each participating site. This process can be quite complex and time-consuming. Since contracts are usually reissued on an annual basis, the coordinating center governing many sites should be prepared for a significant workload. In addition, there are situations in which the contract will need to be translated into another language.
At the host institution, it is critically important for investigators to meet with grants and contracts officials at the initiation of the trial to review the subcontracting process and associated timelines.
Contract negotiations can be very time consuming, so any modifications to existing contractual agreements must be clearly communicated to all parties involved. In the MGTX trial, contract execution averaged 8. The major stumbling blocks for US sites were issues related to indirect cost recovery, which is not offered for direct patient care costs, and issues related to indemnification.
For foreign sites, major issues included the translation of contracts into local languages and currency and other payment issues. Payment mechanisms can vary from trial to trial.
In a pay-for-performance model, common to the pharmaceutical industry, sites are reimbursed for procedures completed on a per-patient basis. In a pay-for-participation model, subcontracts are issued for time and effort of the research team with an expectation that sufficient subjects will be enrolled.
From one perspective, the latter model could be considered less desirable since underperforming sites would receive the same budget as those sites with the best performance. However, in most accounting systems, this latter pay-for-participation arrangement is easier to negotiate and manage for the host institution.
The former pay-for-performance arrangement is more complex and requires that invoices be received with documentation of work completed, per unit of time, in order to reimburse for work completed under the contract. This requires ongoing interaction between staff at the clinic and adjudication with what has been received at the coordinating center.
One approach to make the process easier and more cost-effective is to have invoices prepared by the coordinating center and then forwarded to the participating sites. Sites then sign the invoices and return them to the coordinating center for payment. However, payments to foreign sites are not always simple. Paper checks can be inconvenient and costly to deposit, if they are even accepted. Currency transfer also can be difficult to manage due to the fluctuating exchange rate of the currencies.
This is best tracked using wire transfers. It is also advisable to specify up front that all payments will be made in US dollars for federally funded studies. If a trial drug is to be used, care must be taken to ensure that it can be used in a participating country.
Even if a drug cannot be imported into a specific country, an equivalent substitute may be available. For example, one of the issues encountered during the MGTX trial was related to prednisone. Some countries, including Japan, Taiwan, and the United Kingdom would not permit importation or use of prednisone manufactured in the United States. Therefore, another form of corticosteroid locally obtained prednisolone is being used. Since local drug was being dispensed, pharmacists had to be trained to ensure that the system used to track dosing matched that of the trial protocol 1.
This unexpected issue added further burden and delay in trial initiation at those sites. However, in some situations, an equivalent drug may not be available. In addition, if the drug is to be supplied from a central location, shipping regulations should be thoroughly vetted before the trial is launched. The study drug or intervention may be subject to additional local regulatory approval and different labeling requirements in terms of language, temperature control, etc.
An import license may be needed and high custom costs may result. The drug importation process itself could interrupt the randomization sequence for some trials 8. It is also worthwhile to note that regulations could change during the course of a trial, especially one that has an extended duration; flexibility by the trial leadership and coordinating centers and the ability to adjust are critically important.
In a multicenter international trial, timely transfer of the data from the sites to the data coordinating center and the data and safety monitoring board DSMB or independent data monitoring committee IDMC is extremely important for monitoring safety of the study participants and maintaining data quality and integrity.
A DSMB meeting will have open sessions, which include trial investigators, and closed sessions, which involve only the unblinded trial statistician s or the DSMB alone. The trial sponsor will typically appoint the DSMB members. DSMB members should understand that differential time zones may create a challenge for real-time adverse event reporting.
A plan should be established to deal with any events that occur after-hours. Language barriers may also create obstacles and translating reports from one language to another may add to the delays. We should add that all international investigators involved in the MGTX study have the ability to speak and converse in English; this is likely to be shared by other international endeavors.
It is critically important to routinely monitor site activities as the study progresses. Web-based data entry systems allow for real-time form completion and data quality monitoring. The notification is immediately circulated to a predetermined list of recipients, which usually includes an independent medical monitor and the DSMB.
SAE follow-ups are prompted by reminders until the event is considered resolved. Back-up fax systems may also be established in the unlikely event that the data entry system is inaccessible. Web-based systems are more efficient and cost-effective than providing centers with their own laptops. In addition, data entry mistakes are minimized when using electronic systems as a result of real-time prompts and questions that occur when an unrecognized or illogical response is identified.
Face-to—face time with a representative from the coordinating center helps with compliance and can significantly improve investigator morale. When dealing with a complex protocol or disease, the trial should be able to handle deviations quickly and consistently to minimize the potential impact on trial continuity.
Flexibility among personnel is necessary when conducting trials in different countries. Many of the exceptions or deviations occur because they were not considered in advance. Some cultural differences can create minor deviations. Other deviations can occur due to scheduling issues, which produce results out of the time window originally planned. Items that could impact patient safety must be handled more carefully in comparison to other study items.
These issues must be considered when developing the inclusion and exclusion criteria when designing the trial. The beginnings of a coordinated prioritization of research needs can be seen in the recent increased interest in comparative effectiveness research CER.
CER seeks to identify what works for which patients under what circumstances, providing evidence about the costs and benefits of different medical options. Several speakers and workshop participants raised questions about the ability of the current clinical trials system, which is already showing signs of strain, to absorb a substantial amount of the anticipated CER studies. Many voiced concern regarding the overall organization of clinical research in the United States: how it is prioritized, where it is conducted, who oversees it, how it is funded, who participates, and who staffs it.
Presenters and. These observations, and proposed solutions, informed the discussion over the course of the 2-day workshop. The limited involvement of community physicians in clinical research reduces physician referrals of patients to clinical research studies, as well as the total number of investigators available to conduct the research see the discussion of narrow incentives for physician participation in clinical trials below.
Furthermore, the findings of research conducted in academic medical centers rather than in community settings are less likely to be adopted by physicians in their daily practice. The poor rate of adoption of effective clinical practices is reflected in one study that examined adherence to indicators of health care quality for 30 acute and chronic conditions and preventive care.
Results indicated that American adults receive on average only Woodcock stressed that, to generate relevant research based in clinical practice, community practitioners must be actively involved in the clinical trial process. She suggested it is not surprising that the uptake of evidence-based practices is slow when practitioners are not engaged in the research that supports the changes. In many instances, the characteristics of the study population, their comorbidities and therapeutic regimens, and the setting and conditions under which the trial is conducted bear little resemblance to typical community practice.
Indeed, the outcomes are often quite different as well. It is little wonder that community physicians may be hesitant to modify their treatment practices to reflect clinical findings developed in this manner.
According to Woodcock, the divergence between physicians conducting research and those in community practice is one of the greatest barriers to successfully translating study results into clinical practice. She argued that, to develop a truly learning health care system capable of self-evaluation and improvement, the currently separate systems of clinical research and practice must converge.
Woodcock discussed a number of important obstacles facing investigators conducting research using the current infrastructure. Clinical investi-.
These obstacles include locating funding, responding to multiple review cycles, obtaining Institutional Review Board IRB approvals, establishing clinical trial and material transfer agreements with sponsors and medical centers, recruiting patients, administering complicated informed consent agreements, securing protected research time from medical school departments, and completing large amounts of associated paperwork. As a result of these challenges, many who try their hand at clinical investigation drop out after their first trial.
Woodcock noted that in her experience, successful clinical investigators represent a select subset of clinicians—highly tenacious and persistent individuals with exceptional motivation to complete the clinical trial process.
According to Robert Califf, Vice Chancellor for Clinical Research and Director of the Duke Translational Medicine Institute, some of the challenges to participating in clinical research mentioned by clinical cardiovascular investigators include.
Califf noted that most of these challenges do not involve the actual conduct of a clinical trial and that many investigators say it is not difficult to get patients to participate in trials as long as the critical physician—patient interaction takes place. Investigators also cite the importance of support for research efforts from their home institution. Practitioners face a number of challenges to their involvement in clinical research.
Busy patient practices and the associated billing and reporting. A further barrier is the lack of a supportive clinical research infrastructure, especially in the form of administrative and financial support. For practitioners who become engaged in running a clinical trial and recruiting patients, their financial reimbursement per patient can, in some cases, be less than they would receive from regular practice.
In addition, there is a financial disincentive for physicians to refer their patients to clinical trials. Physicians who do so must often refer those patients away from their care; thus each patient referred represents a lost revenue stream. Patients also face challenges to participating in clinical research. Many workshop participants noted that patients often are unaware of the possibility of enrolling in a clinical trial.
If they are aware of this opportunity, it is often difficult for them to locate a trial. Patients may reside far from study centers; even the largest multicenter trials can pose geographic challenges for those wishing to participate. Moreover, depending on the number of clinic visits required by the study protocol, significant travel and time costs may be associated with participation. In addition, trials designed with narrow eligibility criteria for participation purposely eliminate many patients who might have the disease being studied but are ineligible because of other characteristics e.
As noted, trials often require patients to temporarily leave the care of their regular doctor and receive services from unfamiliar providers. In addition to confronting potentially undesirable interruptions in care, it is understandably difficult for many patients to justify the physical and emotional strain of leaving their regular provider to volunteer for a clinical trial. If a patient reaches the point of enrolling in a clinical trial, the extensive paperwork associated with the informed consent process can be confusing and burdensome.
As discussed later, informed consent forms are developed to meet legal requirements and can contribute to the confusion patients feel regarding the trial and what it entails. In addition, there is sometimes a mistrust of industry-sponsored trials among the public. These feelings of mistrust can further complicate the already difficult decision about whether to join a trial. The increasing trend toward conducting clinical trials outside the United States is an important consideration in discussing ways to improve the efficiency of trials.
The number of patients enrolled in clinical trials. According to Woodcock, when development programs are conducted entirely outside the United States, the FDA questions the extent to which the results can be translated to U.
The applicability of foreign trials results depends on the disease being studied and the state of current clinical practice in that area. Califf suggested that the difficulties inherent in conducting clinical trials in the United States have contributed to the relative decline in U. Citing a recent paper that he coauthored, he noted that one-third of phase III trials for the 20 largest U. For these same firms and studies, a majority of study sites 13, of 24, are abroad Glickman et al.
Califf stated that the situation is the same across study sponsors—NIH, industry, and academia all look to conduct trials internationally. Califf suggested that globalization is a positive trend overall, one in which he and his home organization, the Duke Clinical Research Institute DCRI , are engaged. However, the current situation in which clinical research is being sent abroad just to get trials completed is unsustainable.
One reason for this situation is that clinical trials in a number of other countries cost less than they currently do in the United States Table see also the discussion of costs below. If a large outcome trial requires enrolling tens of thousands of patients, for example, selecting trial sites in Russia or India instead of the United States can result in hundreds of millions of dollars in savings. The overall cost associated with gathering the necessary resources to conduct a clinical trial is an important factor in the choice of a trial site.
For instance, physician salaries in a number of countries are lower than in. In these countries, the charges to clinical trial sponsors for conducting a clinical trial with physician involvement are lower than they would be in the United States. Some also argue that clinical trials conducted outside of the United States are of higher quality because of better adherence to trial protocols and better patient follow-up. Clinical trial costs can vary widely depending on the number of patients being sought, the number and location of research sites, the complexity of the trial protocol, and the reimbursement provided to investigators.
According to Cannon, the exorbitant cost of clinical trials today points to the need to move toward simpler large trials that would study a broader population, include less data, and cost less overall. The federal government funds a large portion of clinical research in the United States, primarily through NIH.
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